GENETIC METABOLIC MYOPATHIES--PHOSPHOFRUCTOKINASE/ACID MALTASE DEFICIENCY

在研究炎症性肌肉疾病（多发性肌炎， 皮肌炎和相关疾病），我们遇到的患者 其他肌肉疾病 我们研究了患有两种遗传病的患者， 代谢性肌病详细：磷酸果糖激酶（PFK）缺乏症， 酸性麦芽糖酶（酸性α-葡糖苷酶或GAA）缺乏。 PFK缺乏症的研究旨在表征遗传性 缺陷和相关的临床表现，在几组 患者由于PFK缺乏症是一种轻微的，以及罕见的 条件，我们已经停止了工作，除了临床咨询或 在会诊时对偶尔就诊的病人进行基因检测。 酸性麦芽糖酶缺乏症更常见，也更严重。 它可以 在婴儿期（庞贝氏症）或以后的生活中是致命的，当肌病 在临床上与肌炎相似的肺部疾病在中年是致命的。 以下研究正在进行中：1）仔细分析最 常见的成人突变。 体外模型系统的研究表明， 多聚嘧啶末端的单碱基突变 内含子1的突变降低了转录率，显然是通过改变 剪接因子的结合，并改变剪接变体的比例， 有利于非生产性mRNA的剪接。 此外，消音器具有 在这个内含子的其他地方被发现，可能是一个候选人， 药物干预来上调该基因。药剂研究 在过去的一年里， 目前还没有好的候选人进行临床试验。2)我们已经确定了一 四名非洲人和一些非洲裔美国人的突变， 确定患者共享所有确定的基因内 多态性（但具有相同突变的法国患者没有）。我们 正在构建一个扩展的单倍型， 关于基因的历史，通过推论， 是谁把它从非洲带到了新世界。3）我们成功地把它带到了非洲。 用逆转录病毒载体进行体外基因转移， 约翰霍普金斯大学的研究人员正在研究一种AAV载体。4)三种不同的GAA 敲除小鼠模型（尝试3个不同的中断位点 以模拟人类疾病的严重程度范围）， 发展计划在受影响的小鼠体内进行基因转移研究。

In the course of studying inflammatory muscle diseases (polymyositis, dermatomyositis, and related diseases), we have encountered patients with other muscle diseases. We have studied patients with two genetic metabolic myopathies in detail: phosphofructokinase (PFK) deficiency, and acid maltase (acid alpha-glucosidase, or GAA) deficiency. The studies of PFK deficiency were aimed at characterizing the genetic defects and the associated clinical picture in several groups of patients. Because PFK deficiency is a mild as well as an infrequent condition, we have ceased work on it except to consult clinically or perform genetic tests on occasional patients in consultation. Acid maltase deficiency is both more frequent and more serious. It can be fatal in infancy (Pompe disease) or later in life, when a myopathy with lung disease clinically similar to myositis is fatal in middle age. The following studies are underway: 1) Careful analysis of the most common adult mutation. Studies with an in vitro model system have shown that a single base mutation in the polypyrimidine tract towards the end of intron 1 reduces the transcription rate, apparently by altering the binding of a splicing factor, and alters the ratio of splice variants to favor the splicing of non-productive mRNA. Furthermore, a silencer has been identified elsewhere in this intron, and may be a candidate for pharmacological intervention to up-regulate this gene. Studies of agents to up-regulate transcription have been carried out in the past year with as yet no good candidate for clinical trial. 2) We have identified a mutation in four African and a number of African-American patients and established that the patients share all identified intragenic polymorphisms (but a French patient with the same mutation does not). We are constructing an extended haplotype with the aim of learning more about the history of the gene and, by inference, the migration of those who bore it from Africa to the new world.3) We have successfully carried out gene transfer in vitro with a retroviral vector, and collaborators at Johns Hopkins are working with an AAV vector. 4) Three different GAA knockout mouse models (3 different sites of interruption in an attempt to mimic the range of severity of the human disease) are under development. Gene transfer studies in vivo in affected mice are planned.